Assessment of radiation in fishes derived from radiocesium in the port of Fukushima Daiichi nuclear power plant.

This study established specialized radiation dose models to evaluate the internal radiation doses derived from 137Cs and 134Cs in fishes in the port of the Fukushima Daiichi Nuclear Power Plant from 2012 to 2023. By August 2018, the activities of 134Cs and 137Cs in fishes decreased at the T1/2 of 176 d and 191 d, respectively. The corresponding mass concentrations were far lower than 1 mg/kg and the chemical toxicity can be negligible. Regarding radiotoxicity, 18,000 Bq/kgfresh weight of 134Cs and 137Cs in grouper Sebastes schlegelii produced 276 µGy/h of radiation dose, which was below the no-effect-dose-rate benchmarks (400 µGy/h). 740,000 Bq/kgfresh weight of 134Cs and 137Cs in greenling Hexagrammos otakii produced 12,600 µGy/h of radiation dose, which was much higher than 400 µGy/h, indicating the possibility of radiation effects. If a person eats these two reported fishes, the resulting committed effective doses for humans are 7.7 µSv and 6.31 mSv, respectively.

ABHD7-mediated depalmitoylation of lamin A promotes myoblast differentiation.

LMNA gene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5) and depalmitoylase α/ß hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of lamin A promotes, whereas high-level palmitoylation of lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of lamin A controls myoblast differentiation.

Preparation and characterization of starch/PBAT film containing hydroxypropyl-ß-cyclodextrin/ethyl lauroyl arginate/cinnamon essential oil microcapsules and its application in the preservation of strawberry.

Cinnamon essential oil (CEO) was emulsified by hydroxypropyl-ß-cyclodextrin/ ethyl lauroyl arginate (HPCD/LAE) complex to make nanoemulsions, which were then incorporated into maltodextrin (MD) to prepare HPCD/LAE/CEO/MD microcapsules by spray drying. The starch/polybutylene adipate terephthalate (starch/PBAT, SP) based extrusion-blowing films containing above microcapsules were developed and used as packaging materials for strawberry preservation. The morphology, encapsulation efficiency, thermal and antibacterial properties of microcapsules with different formulations were investigated. The effects of microcapsules on the physicochemical and antimicrobial properties of SP films were evaluated. When the formula was 4 % HPCD/LAE-3% CEO-10% MD (HL-3C-MD), the microcapsule had the smallest particle size (3.3 µm), the highest encapsulation efficiency (84.51 %) of CEO and the best antibacterial effect. The mechanical and antimicrobial properties of the SP film were enhanced while the water vapor transmittance and oxygen permeability decreased with the incorporation of HL-3C-MD microcapsules. The films effectively reduced the weight loss rate (49.03 %), decay rate (40.59 %) and the total number of colonies (2.474 log CFU/g) and molds (2.936 log CFU/g), thus extending the shelf life of strawberries. This study revealed that the developed SP films containing HPCD/LAE/CEO microcapsules had potential applications in degradable bioactive food packaging materials.

Qingda granule alleviates cerebral ischemia/reperfusion injury by inhibiting TLR4/NF-κB/NLRP3 signaling in microglia.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingda granule (QDG) is effective for treating hypertension and neuronal damage after cerebral ischemia/reperfusion. However, the anti-neuroinflammatory effect of QDG on injury due to cerebral ischemia/reperfusion is unclear. AIM OF THE STUDY: The objective was to evaluate the effectiveness and action of QDG in treating neuroinflammation resulting from cerebral ischemia/reperfusion-induced injury. MATERIALS AND METHODS: Network pharmacology was used to predict targets and pathways of QDG. An in vivo rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) as well as an in vitro model of LPS-stimulated BV-2 cells were established. Magnetic resonance imaging (MRI) was used to quantify the area of cerebral infarction, with morphological changes in the brain being assessed by histology. Immunohistochemistry (IHC) was used to assess levels of the microglial marker IBA-1 in brain tissue. Bioplex analysis was used to measure TNF-α, IL-1ß, IL-6, and MCP-1 in sera and in BV-2 cell culture supernatants. Simultaneously, mRNA levels of these factors were examined using RT-qPCR analysis. Proteins of the TLR4/NF-κB/NLRP3 axis were examined using IHC in vivo and Western blot in vitro, respectively. While NF-κB translocation was assessed using immunofluorescence. RESULTS: The core targets of QDG included TNF, NF-κB1, MAPK1, MAPK3, JUN, and TLR4. QDG suppressed inflammation via modulation of TLR4/NF-κB signaling. In addition, our in vivo experiments using MCAO/R rats demonstrated the therapeutic effect of QDG in reducing brain tissue infarction, improving neurological function, and ameliorating cerebral histopathological damage. Furthermore, QDG reduced the levels of TNF-α, IL-1ß, IL-6, and MCP-1 in both sera from MCAO/R rats and supernatants from LPS-induced BV-2 cells, along with a reduction in the expression of the microglia biomarker IBA-1, as well as that of TLR4, MyD88, p-IKK, p-IκBα, p-P65, and NLRP3 in MCAO/R rats. In LPS-treated BV-2 cells, QDG downregulated the expression of proinflammatory factors and TLR4/NF-κB/NLRP3 signaling-related proteins. Additionally, QDG reduced translocation of NF-κB to the nucleus in both brains of MCAO/R rats and LPS-induced BV-2 cells. Moreover, the combined treatment of the TLR4 inhibitor TAK242 and QDG significantly reduced the levels of p-P65, NLRP3, and IL-6. CONCLUSIONS: QDG significantly suppressed neuroinflammation by inhibiting the TLR4/NF-κB/NLRP3 axis in microglia. This suggests potential for QDG in treating ischemia stroke.

Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin.

Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation.

The effect of Orem's nursing theory on the pain levels, self-care abilities, psychological statuses, and quality of life of bone cancer patients.

OBJECTIVE: This study aims to explore the impact of Orem-based nursing intervention on the pain levels, self-care abilities, psychological statuses, and quality of life in bone cancer patients. METHODS: A total of 91 patients with primary bone cancer admitted to our hospital from January 2019 to January 2020 were randomly placed into one of two groups. The patients in the control group (n=43) underwent routine nursing care, and the patients in the experimental group (n=48) underwent Orem-based nursing care during the perioperative period. The two groups were compared in terms of their postoperative recovery times and treatment effects, and their adverse emotion scores, pain levels, self-care abilities, and quality of life before and after intervention. RESULTS: The treatment efficacy in the two groups was similar, but the postoperative recovery times in the experimental group were shorter than they were in the control group (P < 0.05). Compared with before the intervention, the SDS, SAS, and VAS scores were significantly decreased in both groups (P < 0.05), and their self-care abilities and quality of life were significantly higher (P < 0.05) after intervention. CONCLUSION: Orem-based nursing combined with perioperative care can mobilize patients' initiative, significantly improve patients' adverse emotions and pain levels, shorten their postoperative recovery times, and help improve their self-care abilities and quality of life.

Research on Anti-inflammatory Targets and Mechanisms of alkaloids in Picrasma quassioides Benn Through Network Pharmacology

Abstract This study aimed to investigate the molecular mechanism of Picrasma quassioides Benn against inflammation by means of network pharmacology. The paper will provide a reference for multi-target and multi-channel treatment of inflammation with traditional Chinese medicine. Through screening and analysis, 11 active ingredients and 109 anti-inflammation prediction targets were obtained and constructed a compound-target network. The targets such as VEGFA, TLR4 and STAT3 may play a crucial role. Network enrichment analysis showed that the 109 potential targets constitute a number of pathways or inflammatory reactions closely related to inflammation, including NF-κB signaling pathway and MAPK signaling pathway. The docking results indicated that the binding energy of Picrasidine Y and the inflammatory factors VEGFA is the highest. This study predicted the role of multiple active compounds in the alkaloids of Picrasma in the inflammatory response, and provided a theoretical basis for the anti-inflammatory mechanism of Picrasma

[Analysis of genetic variant in a Chinese pedigree with hereditary factor VIII deficiency].

OBJECTIVE: To explore the genetic basis for a patient with factor VIII deficiency. METHODS: All exons of the F13A1 and F13B genes were amplified by PCR and sequenced directly. The sequencing was performed with a reverse primer if a variant was found. Conservation of variant site was analyzed by the ClustalX software. Four online bioinformatic software including Mutation Taster, PolyPhen-2, PROVEAN and SIFT were used to predict the function of the mutation site. The Swiss-PdbViewer software was applied to analyze the changes in the protein model and intermolecular force. RESULTS: The proband was found to harbor a novel c.515G>C (p.Arg171Pro) variant of the F13A1 gene. The corresponding amino acid Arg171 is conserved among homologous species. Bioinformatic analysis indicated that Arg171Pro variant may affect the protein function. Protein model analysis showed that in the wild-type, there is one hydrogen bond between Arg171 and Pro27; one hydrogen bond between Arg171 and Thr28; two hydrogen bonds between Arg171 and Glu102. When Arg171 was mutated to Pro171, the three hydrogen bonds between Arg171 and Pro27, Glu102 are all disappeared and formed a new benzene ring which might affect the stability of the protein structure. No variant was found in the F13B gene. CONCLUSION: The Arg171Pro variant may account for the decreased FVIII level. Above finding has enriched the spectrum of F13A1 gene variants.

Design and synthesis of novel aza-ursolic acid derivatives: in vitro cytotoxicity and nitric oxide release inhibitory activity.

Aim: Inducible nitric oxide synthase (iNOS) is a validated target for anti-inflammatory treatment. Based on the authors' previous work, novel aza-ursolic acid derivatives were designed and synthesized and their inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) release from RAW264.7 cells was evaluated. Materials & results: 16 novel derivatives were screened for their in vitro inhibitory activity against NO release using Griess assays and the cytotoxicity was evaluated using MTT assays. The presence of furoxan joined to the A-ring of ursolic acid and N-methylpiperazine groups in the lead compound was identified for anti-inflammatory activity, and compound 21b showed 94.96% inhibition of NO release at 100 µM with an IC50 value of 8.58 µM. Conclusion: Compound 21b has potential anti-inflammatory activity with low cytotoxicity that warrants further preclinical study and evaluation.

Characterization of chitosan film with cinnamon essential oil emulsion co-stabilized by ethyl-Nα-lauroyl-l-arginate hydrochloride and hydroxypropyl-ß-cyclodextrin.

To improve the antimicrobial properties of chitosan films, cinnamon essential oil (CEO) nanoemulsion (1% and 3% v/v CEO) stabilized by ethyl-Nα-lauroyl-l-arginate hydrochloride (LAE) alone or co-stabilized by LAE and hydroxypropyl-ß-cyclodextrin (HPCD) were incorporated into chitosan matrix. The micromorphology, physical and antimicrobial properties of the composite films were compared. The dense structure of the CEO nanoemulsion co-stabilized by LAE and HPCD reduced the water vapor permeability and water content. The incorporation of the CEO nanoemulsion co-stabilized by LAE and HPCD, reduced the adverse effects of CEO on the mechanical properties and microstructure of the film, and even slightly increased the tensile strength. In addition, the antimicrobial properties of chitosan films were enhanced due to the encapsulation and emulsification effect of HPCD and LAE on CEO. This work indicated that the prepared chitosan based edible films had the potential to be used in the field of food packaging to improve food safety.

Anti-inflammatory effects of three withanolides isolated from Physalis angulata L. in LPS-activated RAW 264.7 cells through blocking NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalis angulata L. is commonly used in many countries as popular medicine for the treatment of a variety of diseases such as malaria, hepatitis, dermatitis and rheumatism. But the anti-inflammatory active constituents of this medicinal plant and their molecular mechanism are still not elucidated clearly. AIM OF THE STUDY: The aim of the study is to isolate and identify a series of compounds from the ethanolic extract of Physalis angulata L., and to investigate the anti-inflammatory activities in vitro and the molecular mechanism of physagulin A, physagulin C, and physagulin H. MATERIALS AND METHODS: In order to further understand the anti-inflammatory mechanism of the three compounds, their potential anti-inflammatory activities were investigated in vitro in LPS-activated RAW 264.7 macrophage cells by Griess assay, ELISA, Western blot and immunofluorescence methods in the present study. RESULTS: Physagulin A, physagulin C, and physagulin H could not only inhibit the release of NO, PGE2, IL-6 and TNF-α, but also could down-regulate the expression of iNOS and COX-2 proteins. Furthermore, physagulin A, physagulin C, and physagulin H could remarkably block the degradation of IκB-α and the nuclear translocation of NF-κB/p65 in LPS-activated RAW 264.7 cells. However, none of them could inhibit the phosphorylation of MAPKs family proteins ERK, JNK and p38. Thus, the anti-inflammatory actions of physagulin A, physagulin C, and physagulin H were mainly due to the significant inhibition of NF-κB signaling pathway rather than MAPKs signaling pathway. CONCLUSIONS: All the results clearly showed that physagulin A, physagulin C, and physagulin H demonstrated potent anti-inflammatory activity and can be used as novel NF-κB inhibitors. They are potential to be developed as an alternative or complementary agents for inflammatory diseases.

O-GlcNAcylation of MEK2 promotes the proliferation and migration of breast cancer cells.

Mitogen-activated protein kinase kinases are an important part of evolutionary conserved signaling modules that are involved in a variety of cellular processes in response to environmental stimuli. Among them, mitogen-activated protein kinase kinase 2 (MEK2) is the most crucial upstream signaling pathway of ERK1/2 cascade as a therapeutic target for overcoming Ras-driven cancers. However, the mechanisms of MEK2 regulation during tumor progression remain not fully elucidated. Herein, we identified that MEK2 was post-translationally regulated by O-GlcNAcylation. We found that MEK2 associated with OGT and was modified by O-GlcNAc. Mass spectrometry analysis further verified that O-GlcNAcylation of MEK2 occurred at Thr13, which was in the docking domain for specifically identifying its target proteins. While total O-GlcNAcylation stimulated the protein stability and phosphorylation of MEK2, Thr13 O-GlcNAcylation of MEK2 specifically enhanced its Thr394 phosphorylation as well as downstream ERK1/2 activation. Genetic ablation of MEK2 O-GlcNAcylation at Thr13 abrogated its ability to promote the proliferation and migration of breast cancer cells. Together, our data demonstrate that O-GlcNAcylation of MEK2 might be a key regulatory mechanism during tumorigenesis and is a potential therapeutic target for tumor treatment.

FluoroTRAQ: Quantitative Analysis of Protein S-Nitrosylation through Fluorous Solid-Phase Extraction Combining with iTRAQ by Mass Spectrometry.

S-Nitrosylation is an important post-translational modification that occurs on cysteine amino acid and regulates signal transduction in diverse cell processes. Dysregulation of protein nitrosylation has shown close association with cardiovascular and neurological diseases, thus demanding further precise and in-depth understanding. Mass spectrometry-based proteomics has been the method of choice for analyzing S-nitrosylated (SNO-) proteins. However, due to their extremely low expression level and rapid turnover rate, quantitative analysis of the S-nitrosylation at the proteomic level remains challenging. Herein, we developed a novel approach termed FluoroTRAQ, which combined the fluorous solid-phase extraction of SNO-peptides and iTRAQ labeling for the quantitative analysis of the SNO-proteome with high sensitivity and specificity. This new analytical strategy was subsequently applied to examine the dynamic SNO-proteome changes of human umbilical vein endothelial cells upon in vitro S-nitrosoglutathione induction. Our data identified a number of novel SNO-proteins and revealed their temporal modulation as validated by biotin switch assay. Our study offered a practical approach for quantitative analysis of protein S-nitrosylation.

Omipalisib Inhibits Esophageal Squamous Cell Carcinoma Growth Through Inactivation of Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) and ERK Signaling.

BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a life-threatening digestive tract malignancy with no known curative treatment. This study aimed to investigate the antineoplastic effects of omipalisib and its underlying molecular mechanisms in ESCC using a high throughput screen. MATERIAL AND METHODS MTT assay and clone formation were used to determine cell viability and proliferation. Flow cytometry was conducted to detect cell cycle distribution and apoptosis. Global gene expression and mRNA expression levels were determined by RNA sequencing and real-time PCR, respectively. Protein expression was evaluated in the 4 ESCC cell lines by Western blot analysis. Finally, a xenograft nude mouse model was used to evaluate the effect of omipalisib on tumor growth in vivo. RESULTS In the pilot screening of a 1404-compound library, we demonstrated that omipalisib markedly inhibited cell proliferation in a panel of ESCC cell lines. Mechanistically, omipalisib induced G0/G1 cell cycle arrest and apoptosis. RNA-seq, KEGG, and GSEA analyses revealed that the PI3K/AKT/mTOR pathway is the prominent target of omipalisib in ESCC cells. Treatment with omipalisib decreased expression of p-AKT, p-4EBP1, p-p70S6K, p-S6, and p-ERK, therefore disrupting the activation of PI3K/AKT/mTOR and ERK signaling. In the nude mouse xenograft model, omipalisib significantly suppressed the tumor growth in ESCC tumor-bearing mice without obvious adverse effects. CONCLUSIONS Omipalisib inhibited the proliferation and growth of ESCC by disrupting PI3K/AKT/mTOR and ERK signaling. The present study supports the rationale for using omipalisib as a therapeutic approach in ESCC patients. Further clinical studies are needed.

Effects of zein stabilized clove essential oil Pickering emulsion on the structure and properties of chitosan-based edible films.

Clove essential oil (CLO) Pickering emulsions were prepared with zein colloid particles as stabilizer, and the effects of CLO Pickering emulsion incorporation on the structure, mechanical, barrier and antimicrobial properties of chitosan-based edible films were explored. CLO Pickering emulsions with 3% w/v zein and 50% v/v CLO had smaller particle size and more even distribution. Incorporation of CLO Pickering emulsion in the films decreased the water vapor permeability and tensile strength, but the elongation at break firstly increased then decreased with the maximum value of 19.2% when the content of emulsion was 0.4%. Scanning electron microscopy revealed the formation of microstructure-sized holes in the films by the addition of CLO Pickering emulsion. The emulsified oil droplets were uniformly distributed, due to the good compatibility between oil phase and chitosan matrix. The antimicrobial properties of the films were strengthened by CLO Pickering emulsion incorporation and mainly depended on its concentration.

Hypoglycemic Effect of the Degraded Polysaccharides from the Wood Ear Medicinal Mushroom Auricularia auricula-judae (Agaricomycetes).

Auricularia auricula-judae is an important culinary-medicinal mushroom. The A. auricula-judae polysaccharides (AAPs) were prepared from A. auricula-judae in the early stage through alkali extraction and deproteination with the Sevag method, and optimal acid hydrolysis conditions were established by Box-Behnken to prepare the degraded polysaccharides (AAPs-F) from AAPs. In this study, a nonenzymatic glycosylation reaction system was used for the evaluation of the inhibitory effects on the formation of advanced glycation end products (AGEs). In addition, high glucose resistance was assessed by glucose consumption of HepG2 cells and the lifespan of Caenorhabditis elegans under high sugar stress. It was found that both 0.5 mg·mL-1 AAPs and 0.2 mg·mL-1 AAPs-F could significantly inhibit AGE formation in short- and long-term glycosylation (P < .05) in a dose-dependent manner, determined by ultraviolet and fluorospectrophotometry. It indicated activity against AGE formation for different concentrations of AAPs and AAPs-F. AAPs-F at 0.5 mg·mL-1 significantly enhanced the glucose absorption of HepG2 cells by 24.4% (P < .05) in a dose-dependent manner at 24 h, and markedly extended the lifespan of C. elegans by 32.9% (P < 0.05) under high sugar stress conditions. This study demonstrated that the derived hydrolysates produced by the hydrolysis of acid had a prominent effect on the inhibition of AGE formation and relieved the stress state caused by high sugar levels.

Antioxidant and anti-diabetic effects of Auricularia auricular polysaccharides and their degradation by artificial gastrointestinal digestion - Bioactivity of Auricularia auricular polysaccharides and their hydrolysates.

BACKGROUND: Auricularia auricular polysaccharides (AAPs) derived from the dried fruit body of A. auricular are valuable compounds with many bioactivities. This research aimed to investigate the antioxidant and anti- diabetic activities of these polysaccharides and their artificial gastrointestinal fluid hydrolysates (AAPHs). METHODS: Artificially simulated gastrointestinal fluid was used to obtain polysaccharide-de- rived fragments, and a rat model of type 2 diabetes mellitus (T2DM) using a high-fat diet and low-dose streptozotocin (STZ) was established to assess their antioxidant and anti-diabetic effects. RESULTS: It was found that AAPs and AAPHs were both heteropolysaccharides and were comprised of arab- inose, xylose, mannose, 2-deoxy-glucose, glucose and glucosamine, but at different mole ratios. AAPHs was purified by Sephadex G-100 chromatography to produce three fractions, namely, AAPHs1, AAPHs2, and AAPHs3. The molecular weights of these three fractions were 320, 169, and 62 kDa respectively. Both AAPs and AAPHs exhibited the evident ability to enhance the activities of antioxidant enzymes and the level of GSH, while increasing the content of liver glycogen and plasma C-peptide compared with the diabetic model group (p < 0.05). Furthermore, AAPHs could cause a marked improvement in glucose-stimulated GLP-1 secretion from 0 min to 30 min (p < 0.05). CONCLUSIONS: The possible mechanism was that AAPHs could partly restore the STZ-induced impairment of GLP-1 secretion, and inhibit the oxidative stress pathway, and thereby alleviate the progression of diabetes. This data demonstrated that the molecular mole ratio and molecular weight had a definite effect on antioxi- dant and anti-diabetic activities.

Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.

The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.